Effect of conjugation on phase transitions in thermoresponsive polymers: an atomistic and coarse-grained simulation study

Abstract

Using atomistic and coarse-grained molecular dynamics (MD) simulations, we explain the shifts in lower critical solution temperature (LCST)-like phase transitions exhibited by elastin-like peptides (ELPs) upon conjugation to other macromolecules (e.g. collagen-like peptides or CLPs). First, using atomistic simulations, we study ELP oligomers with the sequence (VPGFG) in explicit water, and characterize the LCST-like transition temperature as one at which the ELP oligomers undergo a change in "hydration state". In agreement with past experimental observations of Luo and Kiick, upon anchoring ELP oligomers to a point to mimic ELP oligomers conjugated to another macromolecule, there is an apparent slight shift in the transition temperature to lower values compared to free (unconjugated) ELP oligomers. However, these atomistic simulations are limited to small systems of short ELPs, and as such do not capture the multiple chain aggregation/phase separation observed in experiments of ELPs. Therefore, we utilize phenomenological coarse-grained (CG) MD simulations to probe how conjugating a block of generic-LCST polymer to another rigid unresponsive macromolecular block impacts the transition temperatures at concentrations and length scales larger than atomistic simulations. We find that when multiple LCST polymer chains are conjugated to a rigid unresponsive polymer block, the increased local crowding of the LCST polymers shifts the transition marked by onset of chain aggregation to smaller effective polymer-polymer attraction energies compared to the free LCST polymer chains. The driving force needed for aggregation is reduced in the conjugates compared to free LCST polymer due to reduction in the loss of polymer configurational entropy upon aggregation.

Engineering the Architecture of Elastin‐Like Polypeptides: From Unimers to Hierarchical Self‐Assembly

“…Codon et al. subsequently demonstrated this ELP‐crowding effect in atomistic and coarse‐grained molecular dynamics simulations . Self‐assembly of ELP‐CLP diblocks can also result in additional morphologies, including vesicles and platelets.…”

“…Shorter ELPs, with <10 pentapeptide repeats, are difficult to study due to their lack of phase behavior and the difficulty in synthesizing them recombinantly. Kiick and co‐workers studied the self‐assembly of short ELP sequences by using solid phase peptide synthesis and conjugating the ELP with hydrophilic, triple‐helix‐forming collagen‐like peptides (CLPs) . A fusion of the ELP sequence (VPFGF) 6 with the CLP motif (GPO) 8 showed self‐assembly of nanoparticles 50–200 nm in diameter, at temperatures ranging from 4 to 65 °C.…”

“…Kiick and co-workers studied the self-assembly of short ELP sequences by using solid phase peptide synthesis and conjugating the ELP with hydrophilic, triple-helix-forming collagen-like peptides (CLPs). [74][75][76][77] A fusion of the ELP sequence (VPFGF) 6 with the CLP motif (GPO) 8 showed self-assembly of nanoparticles 50-200 nm in diameter, at temperatures ranging from 4 to 65°C. These results were unexpected because the T t of ELPs (and other thermoresponsive polymers) was thought to always increase when fused to a hydrophilic protein.…”

“…Codon et al subsequently demonstrated this ELP-crowding effect in atomistic and coarsegrained molecular dynamics simulations. [74] Self-assembly of ELP-CLP diblocks can also result in additional morphologies, including vesicles and platelets. Vesicle formation was achieved by using phenylalanine as a guest in the ELP motif, while plateletlike structures were formed when a more hydrophobic amino acid-tryptophan-was used as a guest residue.…”

Next generation protein‐polymer conjugates

“…Despite the lack of a unified approach, MS have been used to determine the local effect of interactions at the protein‐polymer interface level over multiple time and length scales. Additionally, atomistic and phenomenological CG models have been used to explain shifts in LCST‐like phase transitions …”